Epithelial lining fluid (ELF) is often considered to be the site of extracellular pulmonary
infections. During the past 25 years, a limited number of studies have evaluated the intrapulmonary penetration of antifungal, antitubercular,
antiparasitic and
antiviral agents. For
antifungal agents, differences in
drug concentrations in ELF or bronchoalveolar lavage (BAL) fluid were observed among various formulations or routes of administration, and between agents within the same class. Aerosolized doses of
deoxycholate amphotericin B,
liposomal amphotericin B and
amphotericin B lipid complex resulted in higher concentrations in ELF or BAL fluid than after
intravenous administration. The mean concentrations in ELF following
intravenous administration of both
anidulafungin and
micafungin ranged between 0.04 and 1.38 μg/mL, and the ELF to plasma concentration ratios (based on the area under the concentration-time curve for total
drug concentrations) were between 0.18 and 0.22 during the first 3 days of
therapy. Among the
azole agents,
intravenous administration of
voriconazole resulted in the highest mean ELF concentrations (range 10.1-48.3 μg/mL) and ratio of penetration (7.1). The range of mean ELF concentrations of
itraconazole and
posaconazole following
oral administration was 0.2-1.9 μg/mL, and the ELF to plasma concentration ratios were <1. A series of studies have evaluated the intrapulmonary penetration of first- and second-line oral
antitubercular agents in healthy adult subjects and patients with
AIDS. The ELF to plasma concentration ratio was >1 for
isoniazid,
ethambutol,
pyrazinamide and
ethionamide. For
rifampicin (
rifampin) and
rifapentine, the ELF to plasma concentration ratio ranged between 0.2 and 0.32, but in alveolar macrophages the concentration of
rifampicin was much higher (145-738 μg/mL compared with 3.3-7.5 μg/mL in ELF). No intrapulmonary studies have been conducted for
rifabutin. Sex,
AIDS status or smoking history had no significant effects on the magnitude of ELF concentrations of
antitubercular agents. Subjects who were slow acetylators had higher plasma and ELF concentrations of
isoniazid than those who were fast acetylators. Penetration of
dapsone into ELF was very good, with the range of mean ELF to plasma concentration ratios being 0.65-2.91 at individual sampling times over 48 hours. Once-daily dosing of aerosolized
pentamidine resulted in higher concentrations in BAL fluid than after
intravenous administration. The mean BAL concentrations at 15-32 days after once- or twice-monthly administration of aerosolized
pentamidine 300 and 600 mg ranged from 6.5 to 28.4 ng/mL. No differences in
pentamidine BAL concentrations were observed in symptomatic patients who developed
Pneumocystis jirovecii pneumonia compared with patients who did not.
Zanamivir concentrations in ELF were similar in magnitude (range 141-326 ng/mL) following administration by continuous
intravenous infusion (3 mg/hour), oral inhalation (10 mg every 12 hours) and intravenous bolus (200 mg every 12 hours). Data from case reports have suggested that concentrations of
nelfinavir and
saquinavir in ELF are undetectable, whereas
tipranavir and
lopinavir had measureable ELF concentrations (2.20 μmol/L and 14.4 μg/mL, respectively) when these
protease inhibitors were co-administrated with
ritonavir. While the clinical significance of ELF or BAL concentrations remains unknown for this group of
anti-infective agents, the knowledge of
drug penetration into the extracellular space of the lung should assist in re-evaluating and designing specific dosing regimens for use against potential pathogens.